{"doi":"10.1136/rapm-2023-104398","title":"Crystallization of short-acting and intermediate-acting local anesthetics when mixed with adjuvants: a semiquantitative light microscopy analysis","abstract":"<jats:sec>\n                  <jats:title>Introduction</jats:title>\n                  <jats:p>The addition of adjuvants to short-acting local anesthetics (LA) is common practice in clinical routine to speed up block onset and decrease pain on injection. In a previous study, we observed the development of microscopic crystal precipitations after bupivacaine or ropivacaine were mixed with adjuvants; this follow-up study is intended to clarify whether crystallization (A) also occurs in short-acting or intermediate-acting LA-adjuvant mixtures, (B) changes over time, and (C) is associated with the solutions’ pH.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>Lidocaine 2%, prilocaine 2%, mepivacaine 2%, procaine 2% and chloroprocaine 2% were individually mixed with clonidine, dexamethasone, dexmedetomidine, epinephrine, fentanyl, morphine or sodium bicarbonate 8.4% in clinically established ratios. For each mixture, we measured initial pH and recorded crystallization patterns at 0, 15, 30 and 60 min using a standardized, semiquantitative light microscopy approach.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>Lidocaine 2% and mepivacaine 2% plus sodium bicarbonate 8.4%, and mepivacaine 2% plus dexamethasone developed delayed grade 5 crystallization over 1 hour. Prilocaine-based, procaine-based and chloroprocaine-based mixtures showed much less pronounced crystallization, with a maximum of grade 2. Initial pH and grade of crystallization showed weak monotonic relationships at time points t<jats:sub>0</jats:sub>, t<jats:sub>15</jats:sub> and t<jats:sub>30</jats:sub> (ρ=−0.17, 0.31 and 0.32, (all p&gt;0.05)) and a moderate relationship time point t<jats:sub>60</jats:sub> (ρ=0.57 (p=0.0003))</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>Our study revealed high grades of crystallization in lidocaine/mepivacaine-bicarbonate and mepivacaine-dexamethasone mixtures, although these were previously considered safe for local, perineural or neuraxial use. Our findings cast particular doubt on the safety of preparing these formulations for later use.</jats:p>\n               </jats:sec>","journal":"Regional Anesthesia &amp; Pain Medicine","year":2023,"id":672982,"datarank":0.3453877639491069,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.0,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1077555,"name":"Ottokar Stundner","orcid":"0000-0002-2718-9291","position":1,"is_corresponding":false},{"id":1758354,"name":"Heidi Fiegl","orcid":null,"position":2,"is_corresponding":false},{"id":1612650,"name":"Lukas Gasteiger","orcid":null,"position":3,"is_corresponding":false},{"id":1758353,"name":"Elisabeth Hoerner","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Crystallization of short-acting and intermediate-acting local anesthetics when mixed with adjuvants: a semiquantitative light microscopy analysis","abstract":"<jats:sec>\n                  <jats:title>Introduction</jats:title>\n                  <jats:p>The addition of adjuvants to short-acting local anesthetics (LA) is common practice in clinical routine to speed up block onset and decrease pain on injection. In a previous study, we observed the development of microscopic crystal precipitations after bupivacaine or ropivacaine were mixed with adjuvants; this follow-up study is intended to clarify whether crystallization (A) also occurs in short-acting or intermediate-acting LA-adjuvant mixtures, (B) changes over time, and (C) is associated with the solutions’ pH.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>Lidocaine 2%, prilocaine 2%, mepivacaine 2%, procaine 2% and chloroprocaine 2% were individually mixed with clonidine, dexamethasone, dexmedetomidine, epinephrine, fentanyl, morphine or sodium bicarbonate 8.4% in clinically established ratios. For each mixture, we measured initial pH and recorded crystallization patterns at 0, 15, 30 and 60 min using a standardized, semiquantitative light microscopy approach.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>Lidocaine 2% and mepivacaine 2% plus sodium bicarbonate 8.4%, and mepivacaine 2% plus dexamethasone developed delayed grade 5 crystallization over 1 hour. Prilocaine-based, procaine-based and chloroprocaine-based mixtures showed much less pronounced crystallization, with a maximum of grade 2. Initial pH and grade of crystallization showed weak monotonic relationships at time points t<jats:sub>0</jats:sub>, t<jats:sub>15</jats:sub> and t<jats:sub>30</jats:sub> (ρ=−0.17, 0.31 and 0.32, (all p&gt;0.05)) and a moderate relationship time point t<jats:sub>60</jats:sub> (ρ=0.57 (p=0.0003))</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>Our study revealed high grades of crystallization in lidocaine/mepivacaine-bicarbonate and mepivacaine-dexamethasone mixtures, although these were previously considered safe for local, perineural or neuraxial use. Our findings cast particular doubt on the safety of preparing these formulations for later use.</jats:p>\n               </jats:sec>","is_dataset_classified":null,"base_score":2.302585092994046,"endowment":2.302585092994046,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36928300","pmcid":null,"openalex_id":"https://openalex.org/W4327575234","authors":[],"funders":[],"total_grants":0,"fwci":2.2952,"citation_percentile":0.87995129,"influential_citations":0,"citation_trend":[{"year":2024,"count":2},{"year":2025,"count":5},{"year":2026,"count":2}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://syndication.highwire.org/content/doi/10.1136/rapm-2023-104398","host_type":"publisher"},{"url":"https://doi.org/10.1136/rapm-2023-104398","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/36928300","host_type":"repository"}],"fields_of_study":["Anesthesia and Pain Management","Dental Anxiety and Anesthesia Techniques","Anesthesia and Sedative Agents","Humans","Anesthetics, Local","Mepivacaine","Sodium Bicarbonate","Crystallization","Follow-Up Studies","Microscopy","Procaine","Bupivacaine","Lidocaine","Prilocaine","Dexamethasone"],"mesh_terms":["Anesthetics, Local","Bupivacaine","Crystallization","Dexamethasone","Follow-Up Studies","Humans","Lidocaine","Mepivacaine","Microscopy","Prilocaine","Procaine","Sodium Bicarbonate"],"keywords":["Mepivacaine","Medicine","Prilocaine","Anesthesia","Sodium bicarbonate","Lidocaine","Bupivacaine","Crystallization","Procaine","Chemistry","Pharmacology","Anesthesia, Local","Regional Anesthesia","Drug-related Side Effects And Adverse Reactions"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Clean water and sanitation"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-16T11:58:36.546198Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}